Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P₂) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P₁) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC₅₀ value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.     

Combined effects of low-level laser therapy and human bone marrow mesenchymal stem cell conditioned medium on viability of human dermal fibroblasts cultured in a high-glucose medium

Low-level laser therapy (LLLT) exhibited biostimulatory effects on fibroblasts viability. Secretomes can be administered to culture mediums by using bone marrow mesenchymal stem cells conditioned medium (BM-MSCs CM). This study investigated the combined effects of LLLT and human bone marrow mesenchymal stem cell conditioned medium (hBM-MSCs CM) on the cellular viability of human dermal fibroblasts (HDFs), which was cultured in a high-glucose (HG) concentration medium. The HDFs were cultured either in a concentration of physiologic (normal) glucose (NG; 5.5 mM/l) or in HG media (15 mM/l) for 4 days. LLLT was performed with a continuous-wave helium-neon laser (632.8 nm, power density of 0.00185 W/cm² and energy densities of 0.5, 1, and 2 J/cm²). About 10 % of hBM-MSCs CM was added to the HG HDF culture medium. The viability of HDFs was evaluated using dimethylthiazol-diphenyltetrazolium bromide (MTT) assay. A significantly higher cell viability was observed when laser of either 0.5 or 1 J/cm² was used to treat HG HDFs, compared to the control groups. The cellular viability of HG-treated HDFs was significantly lower compared to the LLLT?+?HG HDFs, hBM-MSCs CM-treated HG HDFs, and LLLT?+?hBM-MSCs CM-treated HG HDFs. In conclusion, hBM-MSCs CM or LLLT alone increased the survival of HG HDFs cells. However, the combination of hBM-MSCs CM and LLLT improved these results in comparison to the conditioned medium.     

Effects of an early referral system on liver transplantation for hepatoblastoma at Texas Children's Hospital

The purposes of this study were to analyze the effects of an ERS on time to transplantation and to describe our center's experience with OLT for HB. Patients who received OLT for HB between 2000 and 2013 were included. Patient and allograft characteristics, chemotherapy regimens, and prior surgical therapies were examined. The interval between diagnosis and OLT prior to and following the institution of an ERS for transplant was compared. Survival and tumor recurrence were analyzed. Nineteen patients received OLT for HB (mean age 33 months). All children received grafts from deceased donors. Two patients underwent prior resections. Tumor recurred in four patients (21.1%). Both patients who received salvage transplants experienced post‐OLT recurrence. Three of the four recurrences occurred in spite of adjuvant chemotherapy. There were three deaths: two from metastatic disease. One‐ and five‐yr survivals were 86.1% and 73.8%. After the institution of the ERS, the mean interval between tissue diagnosis and OLT was significantly reduced. Our series of 19 patients demonstrates a 21% recurrence of HB following OLT despite chemotherapy. Five‐yr survival reached 73.8%. A system of early referral can effectively reduce times between diagnosis and transplant.     

The role of toll-like receptors in B-cell development and immunopathogenesis of common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immune deficiency and is characterized by hypogammaglobulinemia, defect in specific antibody response and increased susceptibility to recurrent infections, malignancy and autoimmunity. Patients with CVID often have defects in post-antigenic B-cell differentiation, with fewer memory B cells and impaired isotype switching. Toll-like receptors (TLRs) are expressed on various immune cells as key elements of innate and adaptive immunity. TLR signaling in B cells plays multiple roles in cell differentiation and activation, class-switch recombination and cytokine and antibody production. Moreover, recent studies have shown functional alteration of TLRs responses in CVID patients including poor cell proliferation, impaired upregulation of co-stimulatory molecules and failure in cytokine and immunoglobulin production. The purpose of the present review is to discuss the role of TLRs in B-cell development and function as well as their role in the immunopathogenesis of CVID.     

Effects of GABAergic inhibition on neocortical long-term potentiation in the chronically prepared rat

In this study we investigated the hypothesis whether P2-related differences tested in a visual priming paradigm are associated with theta phase-locking. We recorded the EEG from 31 electrodes and calculated phase-locking index and total power differences for frequencies between 2 and 20 Hz. ERPs (event-related potentials) were analyzed for P1, N1 and P2 components. P2 showed strongest task-related amplitude differences between congruent and incongruent targets. A source analyses was performed for the P2 component using sLoreta that revealed local generators of the P2 in parieto-occipital regions. Phase-locking analyses showed specific effects in the theta range (4-6 Hz) appearing in time windows at around the P2 component. We draw the conclusion that phase-locked theta reflect top-down regulation processes mediating information between memory systems and is in part involved in the modulation of the P2 component.     

Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat

Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.     

Elastic moduli of normal and pathological human breast tissues: an inversion-technique-based investigation of 169 samples

Understanding and quantifying the mechanical properties of breast tissues has been a subject of interest for the past two decades. This has been motivated in part by interest in modelling soft tissue response for surgery planning and virtual-reality-based surgical training. Interpreting elastography images for diagnostic purposes also requires a sound understanding of normal and pathological tissue mechanical properties. Reliable data on tissue elastic properties are very limited and those which are available tend to be inconsistent, in part as a result of measurement methodology. We have developed specialized techniques to measure tissue elasticity of breast normal tissues and tumour specimens and applied them to 169 fresh ex vivo breast tissue samples including fat and fibroglandular tissue as well as a range of benign and malignant breast tumour types. Results show that, under small deformation conditions, the elastic modulus of normal breast fat and fibroglandular tissues are similar while fibroadenomas were approximately twice the stiffness. Fibrocystic disease and malignant tumours exhibited a 3-6-fold increased stiffness with high-grade invasive ductal carcinoma exhibiting up to a 13-fold increase in stiffness compared to fibrogalndular tissue. A statistical analysis showed that differences between the elastic modulus of the majority of those tissues were statistically significant. Implications for the specificity advantages of elastography are reviewed.     

An inverse problem solution for measuring the elastic modulus of intact ex vivo breast tissue tumours

Soft tissue elasticity has been a subject of interest in biomedical applications as an aid to medical diagnosis since the dawn of medicine. More recently, this has led to the concept of elastography with the aim of imaging the spatial distribution of tissue elasticity. Interpreting elastography images requires reliable information pertaining to elastic properties of normal and pathological tissues. Such information is either very limited or not available in the literature. Elastic modulus measurement techniques developed for soft tissues generally require tissue excision to prepare samples for testing. While this may be done with normal tissues, tumour tissue excision is generally not permissible because tumour pathological assessment requires that the tumour be kept intact. To address this limitation, we developed a system to measure the Young's modulus of tumour specimens. The technique consists of indenting the tumour specimen while measuring indentation force and displacements. To obtain the Young's modulus from the measured force-displacement slope, we developed an iterative inversion technique that uses a finite element model of the piecewise homogeneous tissue slice in each iteration. Preliminary elasticity measurement results of various breast tumours are presented and discussed. These results indicate that the proposed method is robust and highly accurate. Furthermore, they indicate that a benign lesion and malignant tumours are roughly five times and ten times stiffer than normal breast tissues respectively.     

PLGA-based monolithic filaments prepared by hot-melt extrusion: In-vitro comparative study

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